In humans, perinatal thyroid hormone (TH) deficiency results in developmental defects that in the nervous system includes mental retardation. TH acts through binding nuclear receptors (TR), which can control gene transcription. Thus, TH regulates development through induction of TH-responsive genes. hairless (hr) has been identified as a TH-responsive gene expressed in the brain, and thus is potentially involved in TH directed development of the nervous system.Our lab has recently defined the biochemical function of Hr as a corepressor that can act through TR. Corepressors are proteins that can repress transcription via a DNA bound transcription factor. Thus, the biochemical characterization of the protein has revealed that Hr may be involved in the mechanism of TR's transcriptional action. The purpose of the proposed research is to investigate the mechanism of Hr-based transcriptional repression, as this will lead to a greater understanding of how TR functions as a transcriptional regulator and how TR, through the recruitment of Hr, may affect nervous system development. I shall investigate Hr-based repression in three ways: 1) Determine the role of each of the repression domains in Hr-based repression; 2) Identify proteins that are recruited by Hr repression domains; 3) Demonstrate that the Hr-interacting protein is involved in Hr-based repression. By discerning the molecular mechanisms of Hr-mediated transcriptional repression, we may discover new avenues for therapeutic design to combat mental retardation as a consequence of altered gene expression.